title: Very late antigen-4 function of myeloblasts correlates with improved overall survival for patients with acute myeloid leukemia.
abstract: Adhesion of acute myeloid leukemia (AML) blasts in the bone marrow microenvironment confers protection from chemotherapy-induced apoptosis. One mechanism for retention of blasts within the bone marrow is adhesion via very late antigen-4 (VLA-4), the alpha(4)beta(1) integrin heterodimer that binds to its main ligands, fibronectin, and vascular cell adhesion molecule-1 (VCAM-1). To examine the relationship of functional expression of VLA-4 to prognosis in AML, we studied marrow samples from 175 adult AML patients who underwent induction chemotherapy with anthracycline and cytarabine on Southwest Oncology Group trials. The studies included flow cytometry and functional in vitro assays for ligand binding and maximal beta(1) activation. VLA-4 expression varied widely, with mean expression 60.6% for alpha(4), and was not significantly associated with response to chemotherapy, relapse-free, or overall survival (OS). However, increased binding of soluble VCAM-1 via VLA-4 was significantly associated with longer OS, corrected for age (P = .033). Estimated 5-year OS was 31% (95% confidence interval, 14%-48%) in 30 patients with soluble VCAM-1 binding greater than or equal to 40%, compared with 10% (confidence interval, 3%-17%) in 72 patients with lower binding. Adhesion and migratory properties of AML blasts thus appear to influence chemosensitivity and therefore may be therapeutic targets.
authors.affiliation: Division of Hematology, University of Washington, Seattle, WA 98109, USA. pbecker@u.washington.edu
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Becker
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Kopecky
authors.forename: Adrianne N
authors.initials: AN
authors.lastname: Wilks
authors.forename: Sylvia
authors.initials: S
authors.lastname: Chien
authors.forename: John M
authors.initials: JM
authors.lastname: Harlan
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Petersdorf
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stirewalt
authors.forename: Thalia
authors.initials: T
authors.lastname: Papayannopoulou
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Appelbaum
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D042381:Granulocyte Precursor Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D015996:Survival Rate; D016896:Treatment Outcome; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D005353:Fibronectins; D039041:Integrin alpha4beta1; D010446:Peptide Fragments; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1